1. Field of the Invention
The present invention relates to compounds that inhibit metalloproteases such as matrix metalloproteases, particularly interstitial collagenases, as well as TNF xcex1-convertase and related sheddases and are therefore useful in the treatment of mammals having disease states alleviated by the inhibition of such metalloproteases.
2. Background Information and Related Disclosures
Matrix metalloproteases (xe2x80x9cMMPsxe2x80x9d) are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. Members of this family of endopeptidase enzymes are present in various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. These ubiquitous extracellular matrix components are present in the linings of joints, interstitial connective tissues, basement membranes, and cartilage. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, bone resorptive diseases (such as osteoporosis), chronic obstructive pulmonary disease, restenosis, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, aneurysmal disease, and in complications of diabetes. MMP inhibition is, therefore, recognized as a good target for therapeutic intervention.
The MMPs share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology. The MMP family currently consists of at least fifteen enzymes, and includes collagenases, stromelysins, gelatinases, matrilysin, metalloelastase, and membrane-type MMP, as discussed in greater detail below.
Interstitial collagenases catalyze the initial and rate-limiting cleavage of native collagen types I, II, and III. Collagen, the major structural protein of mammals, is an essential component of the matrix of many tissues, for example, cartilage, bone, tendon and skin. Interstitial collagenases are very specific matrix metalloproteases which cleave these collagens to give two fragments which spontaneously denature at physiological temperatures and therefore become susceptible to cleavage by less specific enzymes. Cleavage by the collagenases results in the loss of structural integrity of the target tissue, essentially an irreversible process. There are currently three known human collagenases. The first is human fibroblast-type collagenase (HFC, MMP-1, or collagenase-1) that is produced by a wide variety of cells including fibroblasts and macrophages. The second is human neutrophil-type collagenase (HNC, MMP-8, or collagenase-2) which has so far only been demonstrated to be produced by neutrophils. The most recently discovered member of this group of MMPs is human collagenase-3 (MMP-13) which was originally found in breast carcinomas, but has since shown to be produced by chondrocytes. The only collagenase known to exist in rodents is the homolog of human collagenase-3.
The gelatinases include two distinct, but highly related, enzymes: a 72-kD enzyme (gelatinase A, HFG, MMP-2) secreted by fibroblasts and a wide variety of other cell types, and a 92-kD enzyme (gelatinase B, HNG, MMP-9) released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. These gelatinases have been shown to degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectin and insoluble elastin.
Stromelysins 1 and 2 have been shown to cleave a broad range of matrix substrates, including laminin, fibronectin, proteoglycans, and collagen types IV and IX in their non-helical domains.
Matrilysin (MMP-7, PUMP-1) has been shown to degrade a wide range of matrix substrates including proteoglycans, gelatins, fibronectin, elastin, and laminin. Its expression has been documented in mononuclear phagocytes, rat uterine explants and sporadically in tumors. Other less characterized MMPs include macrophage metalloelastase (MME, MMP-12), membrane type MMP (MMP-14), and stromelysin-3 (MMP-11).
Inhibitors of MMPs provide useful treatments for diseases associated with the excessive degradation of extracellular matrix, such as arthritic diseases (rheumatoid arthritis and osteoarthritis), multiple sclerosis, bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, corneal or gastric ulceration, ulceration of the skin, tumor invasion and metastasis, aneurysmal disease such as abdominal aortic aneurysm disease, and aberrant angiogenesis. The involvement of individual collagenases in the degradation of tissue collagens probably depends markedly on the tissue. The tissue distribution of human collagenases suggests that collagenase-3 is the major participant in the degradation of the collagen matrix of cartilage, while collagenase-1 is more likely to be involved in tissue remodeling of skin and other soft tissues. Thus, inhibitors selective for collagenase-3 over collagenase-1 are preferred for treatment of diseases associated with cartilage erosion, such as arthritis, etc.
Some inhibitors of MMP also are known to substantially inhibit the release of tumor necrosis factor (TNF) from cells and therefore may be used in the treatment of conditions mediated by TNF. Such uses include, but are not limited to, the treatment of inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, restenosis, graft versus host reactions and autoimmune disease. Compounds of this invention may inhibit TNF release without inhibiting the MMPs.
In addition to these effects on the release of TNF from cells, MMP inhibitors and related compounds have also been shown to inhibit the release of other biologically active molecules from cells, including soluble receptors (CD30 and receptors for TNF (p55 and p75), IL-6, IL-1 and TSH), adhesion molecules (e.g., L-selectin, ICAM-1, fibronectin) and other growth factors and cytokines, including Fas ligand, TGF-xcex1, EGF, HB-EGF, SCF and M-CSF. The release of such molecules is facilitated by several proteolytic proteins known as sheddases. Inhibition of the release or shedding of such molecules by inhibiting the sheddases may be of benefit in a number of disease states, including rheumatoid arthritis, multiple sclerosis, vascular disease, Type II diabetes, HIV, cachexia, psoriasis, allergy, hepatitis, inflammatory bowel disease, and cancer. Since non-specific inhibition of the shedding enzymes (sheddases) may have opposite pharmacological effects, selectivity will be a particular advantage, e.g., the inhibition of TNF release without the concurrent inhibition of TNF receptor release.
The design and uses of MMP inhibitors is described, for example, in J. Enzyme Inhibition, 2, 1-22 (1987); Drug News and Prospectives, 3(8), 453-458 (1990); Arthritis and Rheumatism, 36(2), 181-189 (1993); Arthritis and Rheumatism, 34(9), 1073-1075 (1991); Seminars in Arthritis and Rheumatism, 19(4), Supplement 1 (February), 16-20 (1990); Drugs of the Future, 15(5), 495-508 (1990); Annals N.Y. Acad. Sci., 157, (1996), and J. Enzyme Inhibition, 2, 1-22 (1987). MMP inhibitors are also the subject of various patents and patent applications, for example, U.S. Pat. Nos. 5,189,178 and 5,183,900, European Published Patent Applications 438 223, 606 426, and 276 436, and Patent Cooperation Treaty International Applications 92/21360, 92/06966, 92/09563, and 94/25434.
In a first aspect, this invention provides hydroxamic acids and their derivatives selected from the group of compounds represented by formula (I): 
wherein:
R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclo, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R1 and R2 together with the carbon atom to which they are attached form a carbocycle or a heterocycle;
R3 is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, heteroalkyl, (diphenylmethyl)alkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R3 together with either R1 or R2 and the atoms to which they are attached forms a heterocycloamino group;
R10 is xe2x80x94NR11OR12 wherein:
R11 and R12 are independently selected from hydrogen, alkyl, or aralkyl;
R20 and R21 are independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaralkyl, or heteroaralkenyl; or R20 and R21 together with the nitrogen atom to which they are attached form a heterocycloamino group or an optionally substituted tetrahydropyridine or hexahydroazepine ring; or either of R20 or R21 together with R3 forms an alkylene group; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that R20 and R21 together with the nitrogen atom to which they are attached do not form a morpholino ring either:
(i) when R1 and R3 are hydrogen and R2 is aralkyl; or
(ii) when R1 and R3 together with the atoms to which they are attached form a tetrahydroisoquinoline ring and R2 is hydrogen.
In a second aspect, this invention provides carboxylic acids selected from the group of compounds represented by formula (I): 
wherein:
R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclo, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R1 and R2 together with the carbon atom to which they are attached form a carbocycle or a heterocycle;
R3 is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, heteroalkyl, (diphenylmethyl)alkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R3 together with either R1 or R2 and the atoms to which they are attached form a heterocycloamino group;
R10 is xe2x80x94OH;
R20 is hydrogen or alkyl; and
R21 is cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaralkyl or heteroaralkenyl; or
R20 and R21 together with the nitrogen atom to which they are attached form either:
(i) a heterocycloamino group substituted with at least one substituent selected from cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl-Qxe2x80x94, aryl-Qxe2x80x94, or heteroaryl-Qxe2x80x94 where Q is an alkylene chain in which a methylene group is optionally replaced by xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)n xe2x80x94 (where n is an integer from 0 to 2), xe2x80x94NRxe2x80x94 (where R is hydrogen or alkyl), xe2x80x94NRaC(O)xe2x80x94, xe2x80x94C(O)NRaxe2x80x94 (where Ra is hydrogen or alkyl), xe2x80x94NRbSO2xe2x80x94, or xe2x80x94SO2NRbxe2x80x94 (where Rb is hydrogen or alkyl);
(ii) a heterocycloamino group that is fused to a cycloalkyl, aryl or heteroaryl ring; or
(iii) an optionally substituted tetrahydropyridine or hexahydroazepine ring;
or either of R20 or R21 together with R3 forms an alkylene group; and
their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that:
(i) R1, R2, and R3 are not all hydrogen; and
(ii) when R1 and R3 are hydrogen and R2 is alkyl, then R21 is not pyridylalkyl.
In a third aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a fourth aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a metalloproteinase inhibitor, comprising administration of a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt.
In a fifth aspect, this invention provides processes for preparing compounds of formula (I).
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropene, pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
xe2x80x9cAlkenylenexe2x80x9d means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, 2-propenylene, and the like.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, or heterocyclo, e.g., acetyl, benzoyl, thenoyl, and the like.
xe2x80x9cAcyloxyxe2x80x9d means a radical xe2x80x94OC(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, or haloalkyl, e.g., acetoxy, 3,3,3-trifluoroacetoxy and the like.
xe2x80x9cAcylaminoxe2x80x9d means a radical xe2x80x94NRC(O)Rxe2x80x2 where R is hydrogen or alkyl and Rxe2x80x2 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl, e.g., acetylamino, trifluoroacetylamino, benzoylamino, methylacetylamino, and the like.
xe2x80x9cSulfonylaminoxe2x80x9d means a radical xe2x80x94NRSO2Rxe2x80x2 where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, haloalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl, e.g., methylsulfonylamino, benzylsulfonylamino, N-methylaminosulfonylamino, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e.g., cyclopropyl, cyclopentyl, cyclohexyl, and the like.
xe2x80x9cCarbocyclexe2x80x9d means a saturated, cyclic group of 3 to 8 ring atoms in which all the ring atoms are carbon, e.g., cyclopentyl, cyclohexyl, and the like.
xe2x80x9cMonosubstituted aminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or an amino protecting group, e.g., methylamino, (1-methylethyl)amino, phenylamino, and the like.
xe2x80x9cDisubstituted aminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or an amino protecting group. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(1-methylethyl)amino, methylbenzylamino, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms and optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, halo, nitro, acyloxy, cyano, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, heteroaryl, heteroaralkyl, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl, optionally substituted phenylalkyl, or heteroaralkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, or heteroaralkyl), xe2x80x94C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl), xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl, optionally substituted phenylalkyl, or heteroaralkyl), xe2x80x94SO2NRRxe2x80x2 (where R and Rxe2x80x2 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl or heteroaralkyl), xe2x80x94COOH, -(alkylene)-COOH, -(alkenylene)-COOH, xe2x80x94COOR a, -(alkenylene)-COORa, -(alkylene)-COORa (where Ra is alkyl, optionally substituted phenylalkyl, or heteroaralkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, -(alkylene)-CONRxe2x80x2Rxe2x80x3, (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, heteroaryl, and heteroaralkyl), xe2x80x94NRC(O)Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl), xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl), or xe2x80x94NRSO2NRxe2x80x2Rxe2x80x3 (where R is hydrogen or alkyl and Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-napthyl and 2-naphthyl, and the derivatives thereof.
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, halo, nitro, cyano, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), xe2x80x94C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), xe2x80x94SO2NRRxe2x80x2 (where R and Rxe2x80x2 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl)], xe2x80x94COOH, -(alkylene)-COOH,-(alkenylene)COOH, xe2x80x94COORa, -(alkenylene)-COORa, -(alkylene)-COORa (where Ra is alkyl, or optionally substituted phenylalkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, -(alkylene)-CONRxe2x80x2Rxe2x80x3, (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), xe2x80x94NRC(O)Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), xe2x80x94NRSO2NRxe2x80x2Rxe2x80x3 (where R is hydrogen or alkyl and Rxe2x80x2 and Rxe2x80x3 are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), or an amino protecting group. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl and benzodiazepin-2-one-5-yl, and the derivatives thereof.
xe2x80x9cOptionally substituted phenylxe2x80x9d means phenyl ring which is optionally substituted with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, halo, nitro, cyano, xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently selected from hydrogen or alkyl), xe2x80x94OR (where R is hydrogen, alkyl or haloalkyl), xe2x80x94COORa (where Ra is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl). Representative examples include, but are not limited to, phenyl, 3-chlorophenyl, 4-(methylthio)phenyl, and the like.
xe2x80x9cHeterocycloaminoxe2x80x9d means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, diphenylmethyl, (diphenylmethyl)alkyl, halo, cyano, acyl, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl], xe2x80x94P(O)(NRbRc)2 (where Rb and Rc are independently selected from alkyl or aralkyl), xe2x80x94COOH, -(alkylene)-COOH, -(alkenylene)-COOH, xe2x80x94COORa, -(alkylene)-COORa, -(alkenylene)COORa (where Ra is alkyl, heteroalkyl, aralkyl, or heteroaralkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, -(alkylene)CONRxe2x80x2Rxe2x80x3, (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), xe2x80x94COCH(Rxe2x80x2)NH2 (where Rxe2x80x2 is a side chain of a natural or unnatural alpha amino acid in which any functional group present may be protected), an amino protecting group, or 1,3-dihydro-2H-1,4-benzodiazepin-2-one wherein the N-1 and C-3 positions may be optionally substituted, independently of each other, with a substituent selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, acyl, and heteroaralkyl. More specifically the term heterocycloamino includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, indolino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 1,2,3,4-tetrahydro-xcex1, -xcex2, or -xcex3, -carbolino, tetrahydroisoquinolyl, and 1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, and the derivatives thereof.
xe2x80x9cOptionally substituted tetrahydropyridine or hexahydroazepine ringxe2x80x9d means a tetrahydropyridine or a hexahydroazepine ring that is optionally substituted with one or two substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, diphenylmethyl, (diphenylmethyl)alkyl, acyl, hydroxy, xe2x80x94COOH, -(alkylene)-COOH, -(alkenylene)-COOH, xe2x80x94COORa, -(alkylene)-COORa, -(alkenylene)-COORa (where Ra is alkyl, heteroalkyl, aralkyl, or heteroaralkyl), xe2x80x94S(O)nR [where n is an integer from 1 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl, aralkyl, or heteroaralkyl], xe2x80x94CONRxe2x80x2Rxe2x80x3, and -(alkylene)-CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl). Representative examples include, but are not limited to, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine, and the like.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cHeterocycloxe2x80x9d means a saturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclo ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acylamino, amino, monosubstituted amino, disubstituted amino, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), xe2x80x94C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl), xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl, aralkyl, or heteroaralkyl], xe2x80x94COOH, -(alkylene)-COOH, xe2x80x94COORa, -(alkylene)-COORa (where Ra is alkyl, heteroalkyl, aralkyl, or heteroaralkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, -(alkylene)-CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl) or an amino protecting group. More specifically the term heterocyclo includes, but is not limited to, tetrahydropyranyl, piperidino, piperazino, morpholino and thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, and the derivatives thereof.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl, cycloalkyl, or cycloalkylalkyl radical as defined above, carrying a substituent selected from xe2x80x94NRaRb, xe2x80x94ORc, xe2x80x94S(O)nRd, xe2x80x94P(O)(ORe)(ORf), xe2x80x94P(O)(ORe)Rg, or xe2x80x94P(O)(NRhRi)2, wherein n is an integer from 0 to 2, Ra is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, or acyl; Rb is hydrogen, alkyl, aryl, aralkyl, acyl, xe2x80x94SO2R (where R is alkyl, haloalkyl, amino, monosubstituted amino or disubstituted amino), xe2x80x94COOR (where R is hydrogen, alkyl, aralkyl, or heteroaralkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, -(alkylene)CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), xe2x80x94P(O)(OR)2 (where each R is independently alkyl, aryl or aralkyl), xe2x80x94P(O)(NRxe2x80x2Rxe2x80x3)2 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or xe2x80x94P(O)(OR)Rxe2x80x2 (where R is alkyl, aryl, or aralkyl and Rxe2x80x2 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); Rc is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, acyl, xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), xe2x80x94P(O)(OR)2 (where each R is independently alkyl, aryl or aralkyl), xe2x80x94P(O)(NRxe2x80x2Rxe2x80x3)2 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or xe2x80x94P(O)(OR)Rxe2x80x2 (where R is alkyl, aryl, or aralkyl and Rxe2x80x2 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); Rd is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, monosubstituted amino, or disubstituted amino; Re and Rf are independently selected from alkyl or aryl; Rg is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; Rh and Ri are independently selected from alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Representative examples include, but are not limited to 2-methoxyethyl, benzyloxymethyl, thiophen-2-ylthiomethyl, and the like;
xe2x80x9cCycloalkylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined above e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
xe2x80x9cAralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
xe2x80x9cAralkenylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkenyl group and Rb is an aryl group as defined above e.g., 3-phenyl-2-propenyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
xe2x80x9cHeteroaralkenylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkenyl group and Rb is a heteroaryl group as defined above e.g., 3-pyridin-3-ylpropen-2-yl, and the like.
xe2x80x9cHeterocycloalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heterocyclo group as defined above e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, or xe2x80x9cheteroaralkyloxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl respectively, as defined above e.g., methoxy, phenoxy, pyridin-2-yloxy, benzyloxy, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9cheterocyclo group optionally mono- or di- substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
xe2x80x9cAmino protecting groupxe2x80x9d refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, 2-trimethylsilylethanesulfonyl (SES), and the like.
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed xe2x80x9cisomersxe2x80x9d. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d.
Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and those that are non-superimposable mirror images of each other are termed xe2x80x9cenantiomersxe2x80x9d. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (xe2x88x92)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a xe2x80x9cracemic mixturexe2x80x9d.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the R1 and R2 substituents in a compound of formula (I) are different, then the carbon to which they are attached is an asymmetric center and therefore the compound of formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4xe2x80x2-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound of formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The naming and numbering of the compounds of this invention is illustrated below. 
The nomenclature used in this application is generally based on the IUPAC recommendations, e.g., a compound of formula (I):
where R10 is xe2x80x94NHOH, R1 is 2-propyl, R2 is hydrogen, R3 is benzyl, the stereochemistry at the carbon to which R1 and R2 are attached is (RS), and R20 and R21 together with the nitrogen atom to which they are attached form a piperidino ring substituted at the 4-position with phenoxy, is named N-hydroxy-2-(RS)-{[benzyl-4-(phenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide;
where R10 is xe2x80x94OH, R1 is Me, R2 and R3 are hydrogen, the stereochemistry at the carbon to which R1 and R2 are attached is (RS), and R20 and R21 together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with 4-chlorophenyl, is named 2-(RS)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionic acid;
where R10 is xe2x80x94NHOH, R1 and R2 form a cyclopentane ring, R3 is hydrogen, the stereochemistry at the carbon to which R1 and R2 are attached is (RS), and R20 and R21 together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with 4-chlorophenyl, is named N-hydroxy-1-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}cyclopentane-1-(RS)-carboxamide;
where R10 is xe2x80x94NHOH, R1 and R3 form a piperidine ring, R2 is hydrogen, the stereochemistry at the carbon to which R1 and R2 are attached is (R), and R20 and R21 together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with phenoxy, is named N-hydroxy-1-[4-(phenoxy)piperazine-1-sulfonyl]piperidine-2-(R)-carboxamide, and
where R10 is xe2x80x94NHOH, R2 is hydrogen, R1 and R3 together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with N,N-dimethylaminocarbonyl and R20 and R21 together with the nitrogen atom to which they are attached form a 1,2,3,6-tetrahydropyridine substituted at the 4-position with 4-fluorophenyl, is named N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.
Representative compounds of this invention are as follows:
I. Compounds of formula (I) where R2=hydrogen, R10=xe2x80x94NR11OR12 where R11 and R12 are hydrogen, and other groups are as defined below are:
and are named as:
1. N-hydroxy-2-(R)-[benzyl-(piperdine-1-sulfonyl)amino]-3-methybutyramide.
5. N-hydroxy-2-[benzyl-(4-chloropiperidine-1-sulfonyl)amino]acetamide.
15. N-hydroxy-2-(RS)-{methyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}acetamide trifluoroacetate salt.
23. N-hydroxy-2-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionamide.
33. N-hydroxy-2-{[4-(3-chlorophenyl)piperazine-1-sulfonyl]amino}acetamide.
41. N-hydroxy-2-(RS)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}butyramide.
50. N-hydroxy-2-(R)-{[4-(5-chloropyridin-2yl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
51. N-hydroxy-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
54. N-hydroxy-2-[4-(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]amino}acetamide.
57. N-hydroxy-2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}propionamide.
59. N-hydroxy-2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
62. N-hydroxy-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-methyl-3-methylthiobutyramide.
66. N-hydroxy-2-(R)-{[4-(4-chlorobenzylcarbomoyl)methyl]piperidine-1-sulfonyl]amino}propionamide.
74. N-hydroxy-2-(R)-{[4-(4-benzyloxyphenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
78. N-hydroxy-2-(R)-{pyridine-3-ylmethyl-[4-(phenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
84. N-hydroxy-2-(R)-{[(4-benzyl-4-hydroxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
90. N-hydroxy-2-(RS)-{methyl-[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-benzyloxypropionamide.
93. N-hydroxy-2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-phenylthiopropionamide.
96. N-hydroxy-2-(R)-{{4-[4-(pyridin-4-ylmehtoxy)phenyl]piperazine-1-sulfonyl}amino}-3-methylbutyramide.
100. N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
103. N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-(4-hydroxyphenyl)propionamide.
114. N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl) piperazine-1-sulfonyl]amino}-3-(pyridin-2-ylthio)propionamide.
125. N-hydroxy-2-(S)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}propionamide.
136. N-hydroxy-2-(R)-{[4-(5-phenylthiazol-2-yl)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
148. N-hydroxy-2-(R)-{[4-(4-phenoxybenzoyl)piperidine-1-sulfonyl]amino}propionamide.
159. N-hydroxy-2-(R)-{[4-(methyl-4-chlorobenzoylaminocarbonyl)piperazine-1-sulfonyl]amino}propionamide.
170. N-hydroxy-2-(R)-{[4-(2-phenylbenzoxal-5-yl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
183. N-hydroxy-2-(R)-{[4-(6-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
196. N-hydroxy-2-(RS)-{2-N,N-dimethylaminoethyl-[4-(phenyl)piperazine-1-sulfonyl]amino}acetamide.
207. N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-2-cyclohexylacetamide.
213. N-hydroxy-2-(R)-{[4-(4-phenoxyphenylaminocarbonyl)piperazine-1-sulfonyl]amino}propionamide.
224. N-hydroxy-2-(R)-{[4-(5-chloropyridin-2yl)piperazine-1-sulfonyl]amino}valeramide.
230. N-hydroxy-2-(R)-{[4-(4-fluorophenyl)piperidine-1-sulfonyl]amino}-2-(4-fluorophenyl)acetamide.
Compounds of formula (I) where R2=hydrogen, R10=xe2x80x94NR11R12 where R11 and R12 are hydrogen, and other groups are as defined below are:
and are named as:
232. N-hydroxy-1-(pyrrolidine-1-sulfonyl)piperidine-2-(R)-carboxamide.
234. N-hydroxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
237. N-hydroxy-1-[4-(pyridin-2yl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
238. N-hydroxy-1-[4-(4-phenoxy)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
239. N-hydroxy-1-[4-(4-phenylthio)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
240. N-hydroxy-1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
249. N-hydroxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]-1,2,3,4-tetrahydroisoquinoline-2-(RS)-carboxamide.
258. N-hydroxy-1-[4-(4-chlorophenyl)piperidine-1-sulfonyl]-4-(pyridin-2-ylcarbonyl)piperidine-2-(RS)-carboxamide.
267. N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]morpholine-2-(R)-carboxamide.
277. N-hydroxy-1-[4-acetyl-1-[4-(6-methylindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(RS)-carboxamide.
289. N-hydroxy-1-[4-(4-chloro-2-methyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
299. N-hydroxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
310. N-hydroxy-4-cyclopropylmethyl-1-[4-(6-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
321. N-hydroxy-4-(morpholine-4-ylcarbonyl)piperazine-1-sulfonyl]-4-(S)-hydroxypiperidine-2-(R)-carboxamide.
331. N-hydroxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
III. Compounds of formula (I) where R3=hydrogen, R10=xe2x80x94NR11OR12 where R11 and R12 are hydrogen, and other groups are as defined below are:
and are named as follows:
337. N-hydroxy-1-{[(4-phenoxy)piperidine-1-sulfonyl]amino}cyclopentane-1-carboxamide.
339. N-hydroxy-4-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}tetrahydropyran-4-carboxamide.
347. N-hydroxy-4-{[4-(4-phenoxy)piperidine1-sulfonyl]amino}tetrahydropyran-4-carboxamide.
351. N-hydroxy-2-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-2-methylpropionamide.
IV. Compounds of formula (I) where R2=hydrogen, R10=xe2x80x94NR11OR12 where R11 and R12 are hydrogen, and other groups are as defined below are:
and are named as:
358. N-hydroxy-2-(RS)-{[benzyl-(methyl-benzyl-aminosulfonyl)amino}-3-methylbutyramide.
360. N-hydroxy-2-(RS)-{[benzyl-(methyl-aminosulfonyl)amino}-3-methylbutyramide.
363. N-hydroxy-1-[(methyl-benzyl-aminosulfonyl)amino]piperidine-2-(R)-craboxamide.
V. Compounds of formula (I) where R2=H, R10=xe2x80x94NR11OR12 and other groups are as defined below are:
and are named as:
365. N-benzyloxy-4-formyl-1-[4(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(RS)-carboxamide.
372. N-hydroxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carcboxamide.
VI. Compounds of formula (I) where R2=H, R10=xe2x80x94NR11OR12 where R11 and R12 are hydrogen and other groups are as defined below are:
and are named as:
375. N-hydroxy-1-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
381. N-hydroxy-4-benzyloxycarbonyl-1-[4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(RS)-carboxamide.
393. N-hydroxy-4-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropridine-1-sulfonyl]-2,2-dimethylthiomorpholine-3-(R)-carboxamide.
399. N-hydroxy-4-[bis(N,N-dimethylaminophosphoryl)]-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(RS)-carboxamide.
VII. Compounds of formula (I) where R2=H, R10=xe2x80x94NR11OR12 where hydrogen and other groups are as defined below are:
and are named as:
401. N-hydroxy-2-(R)-1-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]propionamide.
406. N-hydroxy-2-(R)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-3-methylbutyramide.
VIII. Compounds of formula (I) where R2=H, R10=xe2x80x94OH and other groups are as defined below are:
and are named as:
410. 1-[4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid.
413. 2-(R)-{[4-pyridin-4-ylmethoxyphenyl)piperazine-1-sulfonyl]amino}-3-methylbutyric acid.
427. 1-[(1,2,3,6-tetrahydro-xcex2-carboline)-2-sulfonyl]piperidine-2-(RS)-carboxylic acid
IX. Compounds of formula (I) where R10=xe2x80x94OH and other groups are as defined below are:
and are named as:
429. 2-(RS)-{benzyl-[methyl-(4-biphenylmethyl)aminosulfonyl]amino}-3-methylbutyric acid.
433. 2(R)-[2-phenylethyl-(2-phenylethylaminosulfonyl)amino]propionic acid.
Miscellaneous Compounds:
436. A compound of formula (I) where, R10=xe2x80x94NHOH, R1 and R2=hydrogen, R3 and R20 together=xe2x80x94(CH2)2xe2x80x94 and R21=4-biphenylmethyl is named as N-hydroxy-5-(4-phenoxybenzoyl)-1,2,5-thiodiazolidine-2-acetamide. (361 M+).
437. A compound of formula (I) where, R10=xe2x80x94NHOH, R1 and R2=hydrogen, R3 and R20 together=xe2x80x94(CH2)2xe2x80x94 and R21=4-phenoxybenzoyl is named as N-hydroxy-5-(4-phenoxybenzoyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetamide. (361 M+).
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of formula (I) are preferred.
(I) Hydroxamic Acids and their derivatives: Compounds of formula (I) where R10 is xe2x80x94NR11OR12.
Within this group a preferred group of compounds is that wherein R10 is xe2x80x94NHOH.
Within this preferred group, a more preferred group of compounds is that wherein:
R1 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, or heteroalkyl, more preferably 2-propyl, tert-butyl, 1-hydroxyethyl, tert-butoxymethyl, 2,2-dimethylpropyl, 2-methylpropyl, 1-methylpropyl, n-propyl, benzyl, phenyl, 4-fluorophenyl, cyclohexyl, (1-methyl-1-methylthio)ethyl, phenythiomethyl, benzylthiomethyl, thiophen-2-ylthiomethyl, pyridin-2-ylthiomethyl, 4-(benzyloxycarbonylamino)butyl, or benzyloxymethyl, most preferably 2-propyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, n-propyl, or 4-fluorophenyl;
R2 is hydrogen; and
R3 is hydrogen, alkyl, aralkyl, heteroaralkyl, or heteroalkyl, preferably hydrogen, methyl, N,N-dimethylaminoethyl, pyridin-3-ylmethyl, benzyl, or 2-phenoxyethyl, most preferably hydrogen, N,N-dimethylaminoethyl, or pyridin-3-ylmethyl.
Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R1 and R2 are attached is as shown in FIG. 1 below. 
Another more preferred group of compounds is that wherein R1 and R2 together with the carbon atoms to which they are attached form a carbocycle or heterocycle, preferably a carbocycle with a ring size between 3 to 6 carbon atoms, more preferably 5 or 6 carbon atoms, or a heterocycle of 6 ring atoms containing a single N, O, or S atom with the carbon to which R1 and R2 are attached being in the 4-position of the heterocycle, most preferably cyclopentyl, cyclohexyl, or piperidino where the nitrogen in the piperidino ring is optionally substituted with acyl, xe2x80x94SO2R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl); and
R3 is as described above.
Yet another more preferred group of compounds is that wherein R3 and R1 together with the atoms to which they are attached form a heterocycloamino group, preferably a heterocycloamino group with a ring size of 6 ring atoms and optionally containing a second heteroatom selected from the group consisting of N, O, or S(O)n (where n is an integer from 0-2), preferably at the 4-position with the nitrogen atom to which R3 is attached being in the 1-position of the heterocycloamino group. Representative heterocycloamino groups formed by R3 and R1 include, but are not limited to, piperidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1,-dioxide, 2,2-dimethylthiomorpholino, or piperazino wherein the nitrogen at the 4-position of the piperazino ring is optionally substituted with alkyl, haloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, acyl, xe2x80x94COORa, -(alkylene)-COORa (where Ra is alkyl), xe2x80x94SO2R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), xe2x80x94CONRxe2x80x2Rxe2x80x3, or -(alkylene)-CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), preferably acyl, haloalkyl, xe2x80x94SO2R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), more preferably acetyl, formyl, 2,2,2-trifluoroethyl, aminocarbonyl, tert-butylaminocarbonyl, N,N-dimethylaminocarbonyl, 2,4-difluorophenylaminocarbonyl, N,N-dimethylaminosulfonyl, bis(N,N-dimethylaminophosphoryl), morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl or 1,4-pyrazin-2-ylcarbonyl.
Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R1 and R2 are attached has (R) stereochemistry.
Within the above preferred and more preferred groups, an even more preferred group of compounds is where either:
(i) R20 and R21 are independently hydrogen, alkyl, acyl, aralkyl, aralkenyl or heteroalkenyl;
(ii) R20 and R21 together with the nitrogen atom to which they are attached form a heterocycloamino group, more preferably where R20 and R21 together with the nitrogen atom to which they are attached form a piperidino or piperazino ring where:
the piperidino ring is optionally substituted at the 4-position by aryl, heteroaryl, acyl, xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), xe2x80x94OR (where R is aryl or heteroaryl), or xe2x80x94S(O)nR (where n is an integer from 0-2 and R is aryl or heteroaryl), more preferably phenyl, phenoxy, 4-(imidazol-1-yl)phenoxy, 5-chloropyridin-2-yloxy, 4-chlorophenoxy, 4-fluorophenoxy, 4-chlorobenzoyl, 4-cyanobenzoyl, 4-methylbenzoyl, 4-chlorophenylsulfonyl, phenylthio, pyridin-4-ylthio, pyridin-2-ylthio, benzoxazol-2-yl, benzothiazol-2-ylthio, 5-phenylthiazol-2-yl, 5-fluoroindol-3-yl, 6-chloroindol-3-yl, 5-phenylimidazol-2-yl, benzimidazol-2-yl, 4-methylphenylthio, 4-chlorophenylthio, 4-cyanophenyl, 4-fluorophenyl, 4-fluorobenzoyl, 4-fluorophenylaminocarbonyl, 5-chloroindol-3-yl, 5-chlorobenzotriazol-1-yl, 6-methylindol-3-yl, 5-fluoroindol-3-ylcarbonyl, 6-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, 4-chloroindol-3-yl, 7-methylindol-3-yl, 5-cyanoindol-3-yl, 6-cyanoindol-3-yl, benzothiophen-2-yl, benzothiophen-3-yl, quinolin-3-yl, 5-chlorobenzimidazol-1-yl, pyridin-2-yloxy, 6-chloropyridin-2-yloxy, naphth-1-yl, naphth-2-yl, 1,2,3,4-tetrahydro-xcex2-carbolino, 7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, 8-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, 7-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, or 8-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, most preferably 4-chlorophenoxy, 4-fluorophenoxy, 4-fluorophenyl, 5-chloropyridin-2-yloxy, 6-chloropyridin-2-yloxy, pyridin-2-yloxy, phenoxy, phenylthio, pyridin-4-ylthio, 4-chlorobenzoyl, 5-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, 6-methylindol-3-yl, 5-chloroindol-3-yl, 5-cyanoindol-3-yl, 5-chlorobenzotriazol-1-yl, 1,2,3,4-tetrahydro-xcex2-carbolino, or 6-chloroindol-3-yl; and
the piperazino ring is optionally substituted at the 4-position by aryl, heteroaryl, xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), or xe2x80x94SO2aryl, more preferably 4-chlorophenyl, 5-chloropyridin-2-yl, 4-benzyloxyphenyl, 4-(pyridin-4-yl)methyloxyphenyl, 2-phenylbenzoxazol-5-yl, pyridin-4-yl, 5-trifluoromethyl-pyridin-2-yl, 4-cyanophenyl, 5-nitropyridin-2-yl, 5-bromopyridin-2-yl, 4-biphenylaminocarbonyl, 4-phenoxyphenyl-aminocarbonyl, 4-benzyloxyphenylaminocarbonyl, or 4-chlorophenylaminocarbonyl, most preferably 4-chlorophenyl, 4-benzyloxyphenyl, 5-chloropyridin-2-yl, 4-cyanophenyl, 4-chlorophenylaminocarbonyl, or 2-phenylbenzoxazol-5-yl; or
(iii) R20 and R21 together with the nitrogen atom to which they are attached form 1,2,3,6-tetrahydropyridine ring which is substituted at the 4-position by an aryl or heteroaryl ring, preferably phenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 5-chloroindol-3-yl, 5-fluoroindol-3-yl or 3,4-difluorophenyl, most preferably 4-chlorophenyl, 4-fluorophenyl, 4-fluoro-3-methylphenyl, or 3-chloro-4-fluorophenyl.
(II) Carboxylic Acids: Compounds of formula (I) where R10 is xe2x80x94OH.
Within this group of compounds a preferred group is that wherein:
R1 is hydrogen, alkyl, aryl, aralkyl, or heteroalkyl, preferably alkyl, aryl, or heteroalkyl, more preferably hydrogen, 2-propyl, tert-butyl, 1-hydroxyethyl, tert-butoxymethyl, 2,2-dimethylpropyl, 2-methylpropyl, 1-methylpropyl, propyl, benzyl, phenyl, 4-fluorophenyl, cyclohexyl, (1-methyl-1-methylthio)ethyl, phenythiomethyl, benzylthiomethyl, thiophen-2-ylthiomethyl, pyridin-2-ylthiomethyl, 4-(benzyloxycarbonylamino)butyl, or benzyloxymethyl, most preferably hydrogen, methyl, or 2-propyl;
R2 is hydrogen; and
R3 is hydrogen, alkyl, aralkyl, heteroaralkyl, or heteroalkyl, preferably hydrogen, benzyl, N,N-dimethylaminoethyl, or pyridin-3-ylmethyl, most preferably hydrogen, benzyl or pyridin-3-ylmethyl, provided that R1, R2 and R3 are not all hydrogen.
Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R1 and R2 are attached is as shown in FIG. 1 below. 
Another preferred group of compounds is that wherein R1 and R2 together with the carbon atoms to which they are attached form a carbocycle or heterocycle, preferably a carbocycle with a ring size between 3 to 6 carbon atoms, more preferably 5 or 6 carbon atoms, or a heterocycle of 6 ring atoms containing a single N, O, or S atom with the carbon to which R1 and R2 are attached being in the 4-position of the heterocycle, most preferably cyclopentyl, cyclohexyl, or piperidino ring where the nitrogen in the piperidino ring is optionally substituted with acyl, xe2x80x94SO2R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl); and
R3 is as described above.
Yet another preferred group of compounds is that wherein R3 and R1 together with the atoms to which they are attached form a heterocycloamino group, preferably a heterocycloamino group with a ring size of 6 ring atoms and optionally containing a second heteroatom selected from the group consisting of N, O, or S(O)n (where n is an integer from 0-2), preferably at the 4-position with the nitrogen atom to which R3 is attached being in the 1-position of the heterocycloamino group. Representative heterocycloamino groups formed by R3 and R1 include, but are not limited to, piperidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 2,2-dimethylthiomorpholino, or piperazino wherein the nitrogen at the 4-position of the piperazino ring is optionally substituted with alkyl, haloalkyl, cycloalkylalkyl, acyl, -(alkylene)-COORa (where Ra is alkyl), xe2x80x94SO2R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), xe2x80x94CONRxe2x80x2Rxe2x80x3, or -(alkylene)-CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), preferably acyl, haloalkyl, xe2x80x94SO2R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), more preferably acetyl, formyl, 2,2,2-trifluoroethyl, aminocarbonyl, N,N-dimethylaminocarbonyl, 2,4-difluorophenylaminocarbonyl, N,N-dimethylaminosulfonyl, bis(N,N-dimethylaminophosphoryl), morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, or 1,4-pyrazin-2-ylcarbonyl.
Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R1 and R2 are attached has (R) stereochcmistry.
Within the above preferred groups, a more preferred group of compounds is where either:
(i) R20 is hydrogen or alkyl, preferably hydrogen or methyl; most preferably methyl; and
R21 is aryl, aralkyl, or heteroaralkyl, preferably benzyl, 4-biphenylmethyl,
3-(4-biphenyl)propyl or 2-phenylethyl, most preferably benzyl or
4-biphenylmethyl;
(ii) R20 and R21 together with the nitrogen atom to which they are attached form a heterocycloamino group substituted with an aryl or heteroaryl ring, more preferably where R20 and R21 together with the nitrogen atom to which they are attached form a piperidino or piperazino ring substituted at the 4-position by aryl or heteroaryl, most preferably where: the piperidino ring is substituted by 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-(pyridin-4-ylmethyloxy)phenyl, 4-(pyridin-3-ylmethyloxy)phenyl, 5-chloropyridin-2-yl, 5-chloropyridin-2-yloxy, 6-fluorobenzisothiazol-3-yl, 6-chloroindol-3-yl, 5-chloroindol-1-yl, 5-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, 6-fluoroindol-3-yl, most preferably 4-chlorophenyl, 4-fluorophenyl, 5-chloropyridin-2-yloxy, 6-fluorobenzisothiazol-3-yl, 4-(pyridin-4-ylmethyloxy)phenyl, or 6-fluorobenzisothiazol-3-yl; and
the piperazino is substituted by 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-(pyridin-4-ylmethyloxy)phenyl, 4-(pyridin-3-yl-methyloxy)phenyl, 5-chloropyridin-2-yl, 6-fluorobenzisothiazol-3-yl, 6-chloroindol-3-yl, 5-chloroindol-1-yl, 5-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, or 6-fluoroindol-3-yl, preferably 4-chlorophenyl, 4-fluorophenyl, 6-lluorobenzisothiazol-3-yl, 4-(pyridin-4-yl-methyloxy)phenyl, or 6-fluorobenzisothiazol-3-yl;
(iii) R20 and R21 together with the nitrogen atom to which they are attached form a 1,2,3,6-tetrahydropyridine ring which is substituted at the 4-position by aryl or heteroaryl, more preferably 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-(pyridin-4-ylmethyloxy)phenyl, 4-(pyridin-3-ylmethyloxy)phenyl, 5-chloropyridin-2-yl, 6-fluorobenzisothiazol-3-yl, 6-chloroindol-3-yl, 5-chloroindol-1-yl, or 6-fluoroindol-3-yl, most preferably 4-chlorophenyl, 4-fluorophenyl, or 4-fluoro-3-methylphenyl; or
(iv) R20 and R21 together with the nitrogen atom to which they are attached form a 4heterocycloamino group that is fused to a cycloalkyl, aryl or heteroaryl ring.
Exemplary particularly preferred compounds are:
N-hydroxy-2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methyl-butyramide.
N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-2-(R)-{[4-(4-fluorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-2-(R)-{[4-(4-benzyloxyphenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-methybutyramide.
N-hydroxy-2-(R)-{[4-(2-phenylbenzoxazol-5-yl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-1-[4-(phenoxy)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(phenylthio)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.
N-hydroxy-1-[4-(6-chloroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-4-acetyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfony]piperazine-2-(RS)-carboxamide.
N-hydroxy-2-(R)-3-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}methylvaleramide.
N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-4-methylvaleramide.
N-hydroxy-2-(R)-3-(S)-{[4-(6-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylvaleramide.
N-hydroxy-2-(R)-{[4-(6-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-4,4-dimethylvaleramide.
N-hydroxy-1-[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(5-chloroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(5-chlorobenzotriazol-1-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-4-acetyl-1-[4-(6-methylindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-formylpiperazine-2-(RS)-carboxamide.
N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}valeramide.
N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-4-methylvaleramide.
N-hydroxy-2-(R)-{[4-(4-cyanophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-2-(R)-{[4-(4-chlorophenylaminocarbonyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}valeramide.
N-hydroxy-1-[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.
N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)-piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminosulfonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)-piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-(1,4-pyrazin-2-ylcarbonyl)-piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(morpholin-4-yl-carbonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.
N-hydroxy-2-(R)-(4-fluorophenyl)-2-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}acetamide.
N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]-4-(morpholin-4-ylcarbonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]-4-(morpholin-4-ylsulfonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tctrahydropyridine-1-sulfonyl]-4-(morpholin-4-ylsulfonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminosulfonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminosulfonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-[bis(N,N-dimethylaminophosphoryl)]-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-[bis(N,N-dimethylaminophosphoryl)]-1-[4-(4-fluorophenyl)-piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(2,4-difluorophenylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropiperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-3-oxo-piperazine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-3-oxo-piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-5-hydroxy-1,2,3,6-tetrahydropiperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-methylbutyramide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3,3-dimethylbutyramide.
N-hydroxy-1-[1,2,3,4-tetrahydro-beta-carbolino-2-sulfonyl]piperidine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[7-fluoro-1,2,3,4-tetrahydro-beta-carbolino-2-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-aminocarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]-4-formylpiperazine-2-(R)-carboxamide.
N-hydroxy-4-acetyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-4-tert-butylaminocarbonyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-piperidine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-N-methyl-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)-piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(morpholin-4-ylcarbonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(tert-butoxycarbonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-2-cyclohexylacetamide.
N-hydroxy-2-(R)-{(pyridin-3-ylmethyl)-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-2-(4-fluorophenyl)acetamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(S)-hydroxybutyramide.
N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(S)-hydroxypiperidine-2-(R)-carboxamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonylamino}-2-(4-hydroxyphenyl)acetamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)piperidine-1-sulfonyl]amino}-2-(4-hydroxyphenyl)acetamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-methylvaleramide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-phenylpropionamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(4-hydroxyphenyl)propionamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(S)-methylvaleramide.
N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N-methylaminocarbonyl)piperazine-2-(R)-carboxamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-valeramide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-pentenamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(thien-2-yl)propionamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-methylthiobutyramide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-tert-butoxypropionamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-benzyloxypropionamide.
N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(R)-methylvaleramide.
2-[benzyl-(benzylmethylaminosulfonyl)amino]acetic acid.
2-(R)-{benzyl-[(4-biphenylmethyl)methylaminosulfonyl)]amino]-3-methylbutyric acid.
2-(R)-{[4-(4-chlorophenyl)piperidine-1-sulfonyl]amino}propionic acid.
2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyric acid
1-[4-(6-fluorobenzisothiazol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.
1-[4-(6-chloroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.
1-[4-(4-chlorophenyl)piperidine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxylic acid.
4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]-piperazine-2-(R)-carboxylic acid.
2-(R)-{[4-(4-chlorophenyl)piperazino-1-sulfonyl]amino}propionic acid.
2-(R)-{[4-(4-fluorophenyl)piperazino-1-sulfonyl]amino}acetic acid.
2-(R)-{[4-(4-chlorophenyl)piperazino-1-sulfonyl]amino}acetic acid.
2-(R)-{[4-(pyridin-4-ylmethyloxyphenyl)piperazino-1-sulfonyl]amino}-3-methylbutyric acid.
6-benzyloxycarbonylamino-2-(R)-{[4-(5-chlorophenyl)piperazino-1-sulfonyl]amino}-hexanoic acid.
2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-methylbutyric acid.
1-[4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.
1-[4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.
1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxylic acid.
1-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxylic acid.
1-[6-fluoro-1,2,3,4-tetrahydro-beta-carbolino-2-sulfonyl]piperidine-2-(R)-carboxylic acid.
2-(R)-{[1,2,3,4-tetrahydro-beta-carbolino-2-sulfonyl]amino}propionic acid.
2-(R)-{(pyridin-2-ylmethyl)-[1,2,3,4-tetrahydro-beta-carbolino-2-sulfonyl]amino}propionic acid.
2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-methylvaleric acid.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synththesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
In general, compounds of formula (I) can be prepared from alkyl 2-[(aminosulfonyl)amino]acetates of formula Ia.
Schemes A, B, and C describe alternative methods to generate the compounds of formula Ia.
A compound of formula Ia where R3 can optionally be hydrogen is prepared from an alpha-amino acetate 1 as shown in Scheme A. 
In Step 1, a 2-[(chlorosulfonyl)amino]acetate of formula 2 is prepared, either:
(a) by reacting an alpha-amino acetate 1 (where R is alkyl, preferably methyl, ethyl, or tert-butyl and R3 is as defined in the Summary of the Invention) with sulfuryl chloride in an aprotic organic solvent (e.g., dichloromethane, tetrahydrofuran, dioxane, acetonitrile, and the like). The reaction may be carried out with or without the presence of an organic base (e.g., triethylamine or pyridine). If an organic base is used, the reaction is carried out at temperatures ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C., otherwise it is carried out between 25xc2x0 C. to 80xc2x0 C.; or
(b) by reacting chlorosulfonic acid with an excess amount of compound 1, or with an equimolar amount of compound 1 in the presence of a non-nucleophilic organic base to give a sulfamic acid intermediate. The reaction is carried out in chlorinated hydrocarbons (e.g., dichloromethane, chloroform, and the like) at 0xc2x0 C. to 30xc2x0 C. The sulfamic acid intermediate is then converted to a 2-[(chlorosulfonyl)amino]acetate of formula 2 by reacting it with a suitable chlorinating agent (e.g., phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, preferably phosphorus pentachloride, and the like). The reaction proceeds upon heating at temperatures ranging from 70xc2x0 C. to 110xc2x0 C. Suitable solvents for the reaction are aromatic hydrocarbons such as benzene, toluene, and the like.
In general, compounds of formula 1 are commercially available or they can be prepared by methods well known in the field of organic chemistry. For example, esters of natural and unnatural amino acids such as alanine, valine, pipecolinic acid, etc., are readily available from Aldrich.
Compounds of formula 1 where R1 and R3 together form a morpholino ring can be prepared by following the procedures described in Brown, G. R., Foubister, A. J., Wright, B., J. Chem. Soc. Perk. Trans. I, 2577, (1985) and Kogami, Y., Okawa, K. Bull. Chem. Soc. Jpn., 60, 2963, (1987). Alpha-thiomethyl amino acids can be prepared by following the procedures described in Arnold, L. D., Kalantar, T. H., Vederas, J. C. J. Am. Chem. Soc., 107, 7108, (1985).
Compounds of formula 1 where R3 is not hydrogen can be prepared under reductive amination reaction conditions by reacting a corresponding alpha-amino acetate 1 where R3 is hydrogen with an aldehyde or ketone in the presence of a suitable reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, and the like) and an organic acid (e.g., glacial acetic acid, trifluoroacetic acid, and the like) at ambient temperature. Suitable solvents for the reaction are halogenated hydrocarbons (e.g., 1,2-dichloroethane, chloroform, and the like).
In Step 2, a compound of formula Ia is prepared by reacting a compound of formula 2 either with an excess amount of an amine of formula 3 or with an equimolar amount of the amine 3 in the presence of a non-nucleophilic organic base (e.g., triethylamine or pyridine, preferably pyridine). The reaction is carried out at temperatures ranging from xe2x88x9278xc2x0 C. to 30xc2x0 C., preferably at 0xc2x0 C. Suitable solvents for the reaction are dichloromethane, diethyl ether, tetrahydrofuran, and the like. Alternatively, a compound of formula Ia is prepared by reacting a compound of formula 2 with an excess of an amine of formula 3 or its corresponding ammonium salt in the presence of an excess of a water soluble base (e.g., sodium carbonate, sodium bicarbonate, or sodium hydroxide). Suitable solvents for the reaction are aqueous solvent mixture such as dioxane/water or tetrahydrofuran/water. The reaction is carried out at temperatures ranging from 0xc2x0 C. to 100xc2x0 C., preferably at RT.
Generally, amines of formula 3 are commercially available e.g., benzylamine, N-ethylmethylamine, 4-chlorophenylpiperazine, 4-phenoxypiperidine, 4-(4-methylphenyl)piperazine, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine, etc., are commercially available. Others can be prepared from starting materials such as 1-tert-butoxycarbonyl-4-hydroxypiperidine, 1-tert-butoxycarbonylisonipecotic acid, 1-tert-butoxycarbonylpiperazine, 1-benzyloxycarbonyl-4-piperidone, piperazine etc., by following the literature procedures such as those listed below.
For general piperazine synthesis and arylation, see, Saari, W. S., Halczenko, W., King, S. W., Huff, J. R., Guare, J. P., Hunt, C. A., Randall, W. C., Anderson, P. S., Lott, V. J., Taylor, D. A., Clineschmidt, B.U. J. Med. Chem., 26, 1696, (1983); Kuipers, W., Wijngaarden, I., Knose, C. G., Amstel, M., Tulp, M. I., Zerman, A. J. Med. Chem., 38, 1942, (1995); Verderame, M. J. Med. Chem., 15, 693, (1972); and Herrin, T. R.; Paullik, J. M., Schuber, E. V., Geiszler, A. O. J. Med. Chem., 18, 1216, (1975).
For indole-substituted piperidine analogs, see, Guillaume, J., Dumont, C., Laurent, J., Nedelec, L. Eur. J. Med. Chem., 22, 33, (1987); Perregaard, J., Arnt, J., Bogeso, K. P., Hyttel, J., Sanchez, C. J. Med. Chem., 35, 1092, (1992); Andersen, K., Perregaard, J., Amt, J., Nielsen, J. B., Begtrup, M. J. Med. Chem. 35, 4823, (1992), Bergman, J., Venemalm, L. Tetrahedron, 46, 6061, (1990); and Sasakura, K., Adachi, M., Sugasawa, T. Synth. Comm., 18(3), 265 (1988).
For benzotriazole and benzisoxazole-substituted piperidine analogs, see, Sato, M., Arimoto, M., Ueno, K. J. Med. Chem., 21, 1116, (1978); 4-benzoxazole-2-ylpiperidines Nestor, J. J. Jr., Horner, B. L., Ho, T. L. Jones, G. H., McRae, G. I., Vickery, B. H. J. Med. Chem., 27, 320 (1984); and Strupczewski, J. T., Allen, R. C., Gardner, B. A., Schmid, B. L., Stache, U., Glamkowski, E. J., Jones, M. C., Ellis, D. B., Huger, F. P., Dunn, R. W. J. Med. Chem., 28, 761, (1985) respectively.
For 4-(benzisothiazol-3-yl)piperldines and 4-(indazol-3-yl)piperidines, see, Fink, D. M., Strupczewski, J. T. Tetrahedron Lett., 6525, (1993) and Strupczewski, J. T. European Patent 0135781, 1989.
For benzimidazole-substituted and related piperidine and piperazine analogs, see, Henning, R., Lattrell, R., Gerhards, H. J., Leven, M. J. Med. Chem., 30, 814-9, (1987); Nomoto, Y., Obase, H., Takai, H., Hirata, T., Teranishi, M., Nakamura, J., Kubo, K. Chem. Pharm. Bull., 38(6), 1591, (1990); Nestor, J. J., Horner, B. L., Ho, T. L., Jones, G. H., McRae, G. I., Vickery, B. H. J. Med. Chem., 27, 320, (1984); Chen, J. J., Zhang, Y., Hammond, S., Dewdney, N., Ho, T., Lin, X., Browner, M. F., Castelhano, A. Tetrahedron Lett., 1601 (1996) and Von Geldern, T. W., Hutchins, C., Kester, J. A., Wu-Wong, J. R., Chiou, W., Dixon, D. B., Opgenorth, T. J., J. Med. Chem., 39, 957, (1996).
For 1,2,3,4-tetrahydro xcex3- or xcex2-carbolines, see, Harbert, C. A., Plattner, J. J., Welch, W. M. J. Med. Chem., 23, 635 (1980) and Still, I. W. J., Strautmanis, J. R. Can. J. Cheb., 68, 1408, (1990) and Ho, B. T., Mclsaac, W. M., Tansey, L. W. J. Pham. Sci., 58, 998, (1969).
For 4-arylthiazol-2-ylpiperidines and 4-arylimidazol-2-ylpiperidines, see, Von Geldern, T. W., Hutchins, C., Kester, J. A., Wu-Wong, J. R., Chiou, W., Dixon, D. B., Opgenorth, T. J. J. Med. Chem., 39, 957 (1996).
For hydroxy-substituted pipecolic acid, see, Gillard, J., Abraham, A., Anderson, P. C., Beaulieu, P. L., Bogri, T., Bousquet, Y., Grenier, L., Guse, I., Lavallee, P. J. Org. Chem., 61, 2226, (1996).
For 4-substituted 1,2,3,6-tetrahydropyridine analogs, see, Wustrow, D. J., Wise, L. D. Synthesis, 993, (1991); Perregaard, J., Moltzen, E. K., Meier, E., Sanchez, C. J. Med. Chem., 38, 1998, (1995); and Bolttcher, H., Barnickel, G., Hausbery, H., Hasse, A. F., Seyfied, C. A., Eiermann, V. J. Med. Chem., 35, 4020 (1992).
Alternatively, compound Ia can be prepared in one step as shown in Step 1,2 (alt.) by reacting the alpha-amino acetate 1 with a sulfamoyl chloride 4, utilizing the reaction conditions described in Step 2 above.
The sulfamoyl chloride 4 can be prepared from the corresponding amine 3 by proceeding as described in Step 1 above. It should be understood that if 3 is a heterocycloamino group substituted with an electron rich heteroaromatic ring, then it may become necessary, in some cases, to deactivate the heteroaromatic ring with a deactivating protecting group before carrying out the sulfonylating reaction. This is done to prevent sulfonylation from occurring on the heteroaromatic ring. For example, where 3 is a 4-(indol-3-yl)piperidino group, the indole nitrogen has to be protected by a deactivating protecting group (such as trimethylsilylethanesulfonyl, acetyl, and the like) prior to converting it to the sulfamoyl chloride.
It will be recognized by one skilled in the art that a compound of formula Ia can be converted to a new compound of formula Ia using methods that do not affect the ester and sulfamide groups. For example, a compound of formula Ia where R3 is hydrogen, can be converted to a corresponding compound of formula Ia where R3 is not hydrogen, if required, either:
(a) by reacting compound Ia where R3 is hydrogen with an alkylating agent R3X, (where X is a leaving group such as chloro, bromo, mesylate, triflate, and the like under alkylating conditions) in the presence of a base (e.g., sodium carbonate, potassium carbonate, sodium hydride and the like) and at reaction temperatures ranging from 0xc2x0 C. to 30xc2x0 C. Suitable solvents for the reaction are THF, dioxane, N,N-dimethylfoimamide and the like, or
(b) by reacting compound Ia with a hydroxy compound of formula R3OH in the presence of a trialkylphosphine or a triaryl phosphine, preferably triphenylphosphine, and a dialkyl azodicarboxylate such as diethyl or diisopropyl azodicarboxylate.
Additionally, a compound of formula Ia where R20 and R21 along with the nitrogen atom to which they are attached form a 4-piperidone ring can be reacted with trimethylsilyl trifluoromethanesulfonate and a nucleophile, such as a 3-unsubstituted pyrrole or indole, to give a compound of formula Ia where R20 and R21 along with the nitrogen atom to which they are attached is a 4-substituted-1,2,3,6-tetrahydropyridine ring, a 4,4-disubstituted-piperidino ring, or a 4-hydroxy-4-substituted piperidino ring depending on the reactivity of the nucleophile used. The reaction is carried out in a non-hydroxylic solvent, preferably methylene chloride or acetonitrile, at reaction temperatures ranging from xe2x88x9230xc2x0 C. to 30xc2x0 C.
A compound of formula Ia where R3 is not hydrogen and R21 may optionally be hydrogen, is prepared from an alpha-amino acetate 1 as shown in Scheme B. 
In Step 1, a compound of formula Ia where R3 is not hydrogen and R21 is hydrogen is prepared by proceeding as described in Step 1,2 (alt.) of Scheme A, but substituting a sulfamoyl chloride of formula 5 for a compound of formula 4.
The sulfamoyl chloride of formula 5 is prepared from a corresponding isocyanate, utilizing the reaction conditions such as those described in Klock, J. A. and Leschinsky, K. L., J. Org. Chem, 46, 4028, (1976). The required isocyanate is commercially available or can be prepared by methods known to one skilled in the art.
In Step 2 (optional), a compound Ia where R21 is hydrogen can be converted to a corresponding compound of formula Ia where R21 is not hydrogen, by proceeding as described in Step 3 (optional) of Scheme A.
A compound of formula Ia where R2 is hydrogen and R3 may optionally be hydrogen is prepared from an alpha-hydroxyacetate 8 or its derivative 6 as shown in Scheme C. 
In Step 1, a 2-[(aminosulfonyl)amino]acetate of formula Ia where R is hydrogen is prepared by reacting an acetate derivative of formula 6 where L is a leaving group under alkylating conditions (e.g., para-toluenesulfonate, triflate, and the like) with a mixed sulfamide (R3 is hydrogen) or a cyclic sulfamide (R3 and R20 or R21 form an alkylene chain) of formula 7 at reaction temperatures ranging from xe2x88x9278xc2x0 C. to xe2x88x9230xc2x0 C. The reaction is carried out in the presence of a base (e.g., sodium hydride, potassium tert-butoxide, and the like) in a suitable polar aprotic organic solvent such as diethyl ether, tetrahydrofuran, and the like.
The mixed sulfamide 7 is prepared by heating the commercially available sulfamide (NH2SO2NH2) with an amine of formula 3 (where R20 and R21 are as defined in the Summary of the Invention except hydrogen) in an aqueous medium. The cyclic sulfamide is prepared by reacting an alkylene diamine with sulfuryl chloride in aprotic organic solvent such as tetrahydrofuran.
Alternatively, compound Ia can be prepared in two steps as shown in Step 1 (alternative), by first preparing an N-tert-butoxycarbonyl-2-[(aminosulfonyl)amino]acetate of formula 10 which is then converted to a compound of formula Ia by removal of the N-protecting group. If compound 10 is the tert-butyl ester (i.e. R=tert-butyl), it is hydrolyzed under the reaction conditions utilized for the removal of the tert-butoxycarbonyl group thereby giving compound of formula (I) (where R10=xe2x80x94OH) instead of compound of formula Ia. Compound 10 is prepared by reacting a 2-hydroxyacetate of formula 8 with an N-Boc protected sulfamide of formula 9 under reaction conditions such as those described in Step 3, method (b) of Scheme A.
Compound 9 is prepared by protecting the amino group in a corresponding sulfamide of formula 7 with di-tert-butyl dicarbonate.
The compound Ia where R3 is hydrogen can be converted to a corresponding compound of formula Ia where R3 is not hydrogen, by proceeding as described in Step 3 (optional) of Scheme A.
Schemes D and E describe methods to prepare compounds of formula (I) from compounds of formula Ia.
Compounds of formula (I) where R10 is hydroxy can be prepared by the methods shown in Scheme D. 
In Step 1, a compound of formula (I) where R10 is hydroxy is prepared from a corresponding compound of formula Ia by hydrolysis of the ester group xe2x80x94OR. In general, the hydrolysis is carried out in the presence of an aqueous base (e.g., sodium hydroxide, lithium hydroxide, and the like) in an alcoholic organic solvent such as methanol, ethanol, and the like. However, when compound Ia is optically active and the carbon atom to which R1 and R2 are attached is a chiral center and either R1 or R2 is hydrogen, the hydrolysis is carried out with aqueous lithium hydroxide in order to prevent racemization from occurring at this chiral center. The hydrolysis reaction proceeds either at ambient temperature or upon heating. Furthermore, if compound Ia is an acid labile ester, such as a tert-butyl ester, then the hydrolysis can be carried out in the presence of an acid (e.g., para-toluenesulfonic acid, trifluoroacetic acid, dry hydrochloric acid, and the like) and in an inert organic solvent such as methylene chloride, benzene, and the like.
Alternatively, compound (I) where R10 is hydroxy may be prepared directly from the alpha-amino acid 11 (Z=hydrogen) or its corresponding salt (Z=sodium, ammonium, and the like) as shown in Step 1 (alt.). The acid 11 or its salt is first solubilized with a suitable solubilizing agent such as trimethylsilylcyanide and then reacted with a sulfamoyl chloride of formula 4.
Compounds of formula (I) where R10 is an xe2x80x94NR11OR12 group where R11 and R12 are as defined in the Summary of the Invention are prepared by the methods shown in Scheme E. 
Method (a)
In Step 1, a compound of formula (I) where R11 and R12 are as defined in the Summary of the Invention except R12 is not hydrogen is prepared by reacting a corresponding acid compound of formula (I) (where R10=xe2x80x94OH) with an N,O-disubstituted hydroxylamine (e.g., N,O-dimethylhydroxylamine, and the like) or an 0-substituted hydroxylamine (e.g., O-benzylhydroxylamine, O-tert-butylhydroxylamine, and the like). The reaction is carried out in the presence of a coupling agent (e.g., N,N-dicyclohexylcarbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylamino-propyl)carbodiimide, and the like), an organic base (e.g., dimethylamino-pyridine, triethylamine, pyridine, N-methylmorpholine, and the like) and optionally hydroxybenzotriazole. The reaction is carried out at temperatures ranging from 0xc2x0 C. to 40xc2x0 C., preferably ambient temperature. Suitable solvents for the reaction are methylene chloride, dichloroethane, DMF, and the like.
In Step 2, (optional), a compound of formula (I) where R12 is hydrogen is prepared from the corresponding compound of formula (I) where R12 is not hydrogen by removal of the R12 group. The reaction conditions utilized depend on the nature of the R12 group e.g., if R12 is tert-butyl, then the reaction is carried out in an inert solvent such as dichloromethane, in the presence of an acid (e.g., dry hydrogen chloride, trifluoroacetic acid, and the like) at 0xc2x0 C. to 25xc2x0 C. If R12 is benzyl, then hydrogenolysis conditions utilizing a metal catalyst such as palladium in an inert solvent such as ethyl acetate or tetrahydrofuran are required.
Alternatively, a compound of formula (I) where R11 and R12 are both hydrogen can be prepared by reacting a corresponding acid compound of formula (I) (where R10=xe2x80x94OH) with an O-substituted hydroxylamine such as O-tert-butyldimethylsilylhydroxylamine, followed by treatment with an acid as described above. It will be recognized by one of ordinary skill in the art that compounds of formula (1) where either R11 or R12 is not hydrogen can be prepared by other procedures well known in the art. For example, a compound of formula (I) where R11 is not hydrogen can be prepared by alkylating the corresponding compound of formula (I) where R11 is hydrogen under the reaction conditions described in Scheme A above.
Method (b)
A compound of formula (I) where R11 is as defined in the Summary of the Invention and R12 is not hydrogen can be prepared by reacting an O-substituted or an N,O-disubstituted-N-hydroxy-2-amino acetamide of formula 13 with a sulfamoyl chloride 4 under the reaction conditions described in Step 1, 2 (alt.) of Scheme A. Compound 13 is prepared by proceeding as described in method (a) (above) but substituting a suitable orthogonally N-protected amino acid (e.g., N-CBZ-glycine or N-BOC-alpha amino isobutyric acid) for an acid of formula (I), followed by removal of the alpha amino protecting group.
Method (c)
A compound of formula (I) where R10 is xe2x80x94NR11OH (where R11 is as defined in the Summary of the Invention) can also be prepared by reacting an acyl derivative of formula 14 where Y is a leaving group under acylating conditions (e.g., chloro, succinimido, and the like) with a suitably protected hydroxylamine (e.g., N,O-bis-trimethylsilylhydroxylamine, N-methylhydroxylamine), or an aqueous solution of hydroxylamine. The reaction is carried out at reaction temperatures ranging from xe2x88x9230xc2x0 C. to 25xc2x0 C. and in a suitable organic solvent such as methylene chloride, tetrahydrofuran, tert-butanol, and the like. When N,O-bis(trimethylsilyl)hydroxylamine is used, compound (I) where R10 is xe2x80x94NHOH is obtained directly since the trimethylsilyl group is cleaved during the acidic workup or upon the addition of methanol to the reaction mixture.
The acyl derivative 14 can be prepared from a corresponding compound of formula (I) where R10 is hydroxy by methods known to those of ordinary skill in the art. For example, compound 14 where Y is chloro can be prepared by reacting compound (I) where R10 is hydroxy with a chlorinating agent such as oxalyl chloride in a suitable organic solvent such as methylene chloride.
Method (d)
A compound of formula (I) where R10 is xe2x80x94NHOH can be prepared directly by reacting a methyl 2-[(aminosulfonyl)amino]acetate of formula Ia where at least one of R1 and R2 is hydrogen with hydroxylamine by the method described in Naruse et. al., J.Org. Chem., 59, 1358, (1994).
Scheme F describes the method to generate compounds of Formula (If) below: 
wherein R is hydrogen or a pharmaceutically acceptable salt ion. 
In Step 1, methyl 2-(R)-[(1,2,3,4-tetrahydro-beta-carbolino-2-sulfonyl)amino]propionate (formula 16) is prepared by reacting the sulfamoyl oxazolidone reagent of formula 15 with (1,2,3,4)-tetrahydro-beta-carboline at between 25xc2x0 C. to 100xc2x0 C., preferably at 80xc2x0 C., in a polar aprotic organic solvent (e.g. acetonitrile, tetrahydrofuran, dichloromethane and the like) until the reaction is judged complete by HPLC analysis.
The D-alanine methyl ester sulfamoyl oxazolidone reagent of formula 15 is prepared by combining 2-chloroethanol with chlorosulfonyl isocyanate in a polar aprotic organic solvent (e.g. acetonitrile, tetrahydrofuran, dichloromethane and the like), followed by the addition of D-alanine methyl ester. The reaction is carried out in the presence of an organic base (e.g. N-methylmorpholine, triethylamine, or pyridine) from xe2x88x9225xc2x0 C. to 50xc2x0 C., preferably at 25xc2x0 C., as described in Dewynter, G., Abdaoui, M., Regainia, Z., Montero, J.-L. Tetrahedron, 1996, 52, 14217.
In Step 2, the compound of formula (If) where R is H is prepared by sapponification of the ester of formula (If) in an alcoholic solvent (e.g. ethanol, isopropanol and the like) in the presence of a water soluble strong base (e.g. lithium hydroxide, sodium hydroxide, and the like). The reaction is carried out at between xe2x88x9225xc2x0 C. to 25xc2x0 C., preferably at 0xc2x0 C.
In Step 3, the compound of formula (If) where R is Na is prepared by reacting the free carboxylic acid of formula (If) where R is H with a water soluble base (e.g. sodium bicarbonate, sodium hydroxide, sodium carbonate, and the like). The reaction is carried out in an alcoholic solvent (e.g. ethanol, isopropanol and the like) at between xe2x88x9225xc2x0 C. to 75xc2x0 C., preferably at 25xc2x0 C.
A detailed description of the synthesis of sodium 2-(R)-[(1,2,3,4-tetrahydro-beta-carbolino-2-sulfonyl)amino]propionate by this method is given in Example 38.
The hydroxamic acids and the carboxylic acids of formula (I) inhibit mammalian matrix metalloproteases (MMP""s), such as the stromelysins, gelatinases, matrilysin, collagenases and human metalloelastase. The compounds and compositions containing them are therefore useful in the treatment of diseases associated with the MMP-induced excessive degradation of matrix and connective tissue within the mammal, such as arthritis (rheumatoid arthritis and osteoarthritis), multiple sclerosis, bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, corneal and gastric ulceration, ulceration of the skin, tumor invasion and metastasis, aneurysmal disease, and aberrant angiogenesis.
The compounds of formula (I) substantially inhibit the release of tumor necrosis factor (TNF) from cells, and are therefore useful for the treatment of conditions mediated by TNF, for example inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, restenosis, graft versus host reactions and autoimmune disease. The compounds of the present invention may also inhibit the release of TNF without significant inhibition of the MMP""s.
The compounds of this invention are therefore useful for treating a number of disease states, for example rheumatoid arthritis, multiple sclerosis, vascular disease, Type II diabetes, HIV, cachexia, psoriasis, allergy, hepatitis, inflammatory bowel disease, and cancer.
The ability of the compounds of formula (I) to inhibit matrix metalloprotease activity, such as the activity of collagenase-1, -2 and 3, stromelysin-1, gelatinases A and B, matrilysin and human metalloelastase may be demonstrated by a variety of in vitro assays known to those of ordinary skill in the art, such as the assay described in the MMP Enzymatic Assay described in FEBS, 296, 263, (1992) or modifications thereof as described in more detail in Example 32. It may also be assayed by the interleukin-1 stimulated cartilage explant assay and cartilage plug implantation assay as described in more detail in Examples 33 and 34.
The ability of the compounds of Formula (I) to inhibit the release of TNF may be assayed by an in vitro assay such as the TNF Monomac 6 assay and by in vivo assays such as the LPS induced TNF release assay and the TNF Receptor Shedding Immunoassay as described in more detail in Examples 35, 36, and 37.
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. The drug can be administered more than once a day, preferably once or twice a day.
Therapeutically effective amounts of compounds of formula I may range from approximately 0.05-35 mg per kilogram body weight of the recipient per day; preferably about 0.3-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 21 mg to 1.4 g per day.
In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aide administration, and do not adversely affect the therapeutic benefit of the compound of formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington""s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of formula I based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of formula I are described in Example 30.